Sammanfattning

Despite decades of progress in primary prevention and treatment of acute coronary syndromes and strokes, cardiovascular disease (CVD) remains the leading cause of death and loss of disability-adjusted life years in Western countries. In this thesis, we sought to identify risk stratifying factors beyond the traditional measures of body mass index (BMI) and dyslipidemia. In particular, we focused on the role of hepatic steatosis in obesity, and on the family history of patients with hyperlipidemia. We quantified circulating metabolites during an oral glucose tolerance test in BMI-discordant (ΔBMI ≥ 3 kg/m2) monozygotic twin pairs based on the presence of concomitant liver fat discordance. Liver fat -discordant cotwins exhibited greater putatively atherogenic differences in metabolomic parameters across a wide range of molecular classes, including lipoproteins, fatty acids, amino acids and glycoproteins. We also observed several putatively atherogenic differences between liver fat -concordant twin pairs, suggesting that increased BMI without concomitant liver fat accumulation may not be entirely neutral with respect to CVD risk. We performed the first comprehensive genotyping analysis of familial combined hyperlipidemia (FCH), a common familial hyperlipidemia typically characterized by elevations in total cholesterol or triglycerides. We observed rare high-impact variants in the APOE or APOA5 genes in only a few (3%) of hyperlipidemic family members. Almost a third of hyperlipidemic family members had elevated polygenic burden for LDL-C or triglycerides, similar to population samples with comparable lipid levels. Next, we estimated incident CVD risk in an overlapping cohort of hyperlipidemic families. We focused on common familial hyperlipidemias characterized by high LDL cholesterol or triglyceride levels after excluding individuals with monogenic FH. In our study, such familial hyperlipidemias conferred increased coronary artery disease and CVD risk, but the elevation in risk was similar to that observed in population-ascertained hyperlipidemias. Additionally, we observed highly similar lipidomic profiles consisting of 151 circulating lipid species between individuals with familial and population-ascertained hyperlipidemias. Our results add to existing support for hepatic steatosis as a more discerning stratifying CVD risk factor among individuals with increased BMI. Our findings on FCH and familial aggregation of high LDL cholesterol or triglyceride levels suggest that they share similar and overlapping pathophysiology with common population-ascertained hyperlipidemias, and may not confer differential CVD risk.
Originalspråkengelska
Handledare
  • Palotie, Aarno, Handledare
  • Ripatti, Samuli, Handledare
  • Pietiläinen, Kirsi, Handledare
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-5564-1
Elektroniska ISBN978-951-51-5565-8
StatusPublicerad - 2019
MoE-publikationstypG5 Doktorsavhandling (artikel)

Vetenskapsgrenar

  • 3121 Inre medicin
  • 3111 Biomedicinska vetenskaper
  • 1184 Genetik, utvecklingsbiologi, fysiologi

Citera det här

@phdthesis{9cd37cf083f2411186ed7365a817df73,
title = "Genomic, metabolomic and clinical profiling of dyslipidemia in families",
abstract = "Despite decades of progress in primary prevention and treatment of acute coronary syndromes and strokes, cardiovascular disease (CVD) remains the leading cause of death and loss of disability-adjusted life years in Western countries. In this thesis, we sought to identify risk stratifying factors beyond the traditional measures of body mass index (BMI) and dyslipidemia. In particular, we focused on the role of hepatic steatosis in obesity, and on the family history of patients with hyperlipidemia. We quantified circulating metabolites during an oral glucose tolerance test in BMI-discordant (ΔBMI ≥ 3 kg/m2) monozygotic twin pairs based on the presence of concomitant liver fat discordance. Liver fat -discordant cotwins exhibited greater putatively atherogenic differences in metabolomic parameters across a wide range of molecular classes, including lipoproteins, fatty acids, amino acids and glycoproteins. We also observed several putatively atherogenic differences between liver fat -concordant twin pairs, suggesting that increased BMI without concomitant liver fat accumulation may not be entirely neutral with respect to CVD risk. We performed the first comprehensive genotyping analysis of familial combined hyperlipidemia (FCH), a common familial hyperlipidemia typically characterized by elevations in total cholesterol or triglycerides. We observed rare high-impact variants in the APOE or APOA5 genes in only a few (3{\%}) of hyperlipidemic family members. Almost a third of hyperlipidemic family members had elevated polygenic burden for LDL-C or triglycerides, similar to population samples with comparable lipid levels. Next, we estimated incident CVD risk in an overlapping cohort of hyperlipidemic families. We focused on common familial hyperlipidemias characterized by high LDL cholesterol or triglyceride levels after excluding individuals with monogenic FH. In our study, such familial hyperlipidemias conferred increased coronary artery disease and CVD risk, but the elevation in risk was similar to that observed in population-ascertained hyperlipidemias. Additionally, we observed highly similar lipidomic profiles consisting of 151 circulating lipid species between individuals with familial and population-ascertained hyperlipidemias. Our results add to existing support for hepatic steatosis as a more discerning stratifying CVD risk factor among individuals with increased BMI. Our findings on FCH and familial aggregation of high LDL cholesterol or triglyceride levels suggest that they share similar and overlapping pathophysiology with common population-ascertained hyperlipidemias, and may not confer differential CVD risk.",
keywords = "Dyslipidemias, +genetics, +metabolism, Liver, Adiposity, Hyperlipidemia, Familial Combined, Hyperlipidemias, Atherosclerosis, Biomarkers, Body Mass Index, Cardiovascular Diseases, Cholesterol, Coronary Artery Disease, Lipids, Obesity, Risk Assessment, Risk Factors, Triglycerides, Twins, Monozygotic, 3121 Internal medicine, 3111 Biomedicine, 1184 Genetics, developmental biology, physiology",
author = "Joel R{\"a}m{\"o}",
note = "M1 - 140 s. + liitteet",
year = "2019",
language = "English",
isbn = "978-951-51-5564-1",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "Helsingin yliopisto",
number = "76/2019",
address = "Finland",

}

Genomic, metabolomic and clinical profiling of dyslipidemia in families. / Rämö, Joel.

Helsinki : Helsingin yliopisto, 2019. 140 s.

Forskningsoutput: AvhandlingDoktorsavhandling

TY - THES

T1 - Genomic, metabolomic and clinical profiling of dyslipidemia in families

AU - Rämö, Joel

N1 - M1 - 140 s. + liitteet

PY - 2019

Y1 - 2019

N2 - Despite decades of progress in primary prevention and treatment of acute coronary syndromes and strokes, cardiovascular disease (CVD) remains the leading cause of death and loss of disability-adjusted life years in Western countries. In this thesis, we sought to identify risk stratifying factors beyond the traditional measures of body mass index (BMI) and dyslipidemia. In particular, we focused on the role of hepatic steatosis in obesity, and on the family history of patients with hyperlipidemia. We quantified circulating metabolites during an oral glucose tolerance test in BMI-discordant (ΔBMI ≥ 3 kg/m2) monozygotic twin pairs based on the presence of concomitant liver fat discordance. Liver fat -discordant cotwins exhibited greater putatively atherogenic differences in metabolomic parameters across a wide range of molecular classes, including lipoproteins, fatty acids, amino acids and glycoproteins. We also observed several putatively atherogenic differences between liver fat -concordant twin pairs, suggesting that increased BMI without concomitant liver fat accumulation may not be entirely neutral with respect to CVD risk. We performed the first comprehensive genotyping analysis of familial combined hyperlipidemia (FCH), a common familial hyperlipidemia typically characterized by elevations in total cholesterol or triglycerides. We observed rare high-impact variants in the APOE or APOA5 genes in only a few (3%) of hyperlipidemic family members. Almost a third of hyperlipidemic family members had elevated polygenic burden for LDL-C or triglycerides, similar to population samples with comparable lipid levels. Next, we estimated incident CVD risk in an overlapping cohort of hyperlipidemic families. We focused on common familial hyperlipidemias characterized by high LDL cholesterol or triglyceride levels after excluding individuals with monogenic FH. In our study, such familial hyperlipidemias conferred increased coronary artery disease and CVD risk, but the elevation in risk was similar to that observed in population-ascertained hyperlipidemias. Additionally, we observed highly similar lipidomic profiles consisting of 151 circulating lipid species between individuals with familial and population-ascertained hyperlipidemias. Our results add to existing support for hepatic steatosis as a more discerning stratifying CVD risk factor among individuals with increased BMI. Our findings on FCH and familial aggregation of high LDL cholesterol or triglyceride levels suggest that they share similar and overlapping pathophysiology with common population-ascertained hyperlipidemias, and may not confer differential CVD risk.

AB - Despite decades of progress in primary prevention and treatment of acute coronary syndromes and strokes, cardiovascular disease (CVD) remains the leading cause of death and loss of disability-adjusted life years in Western countries. In this thesis, we sought to identify risk stratifying factors beyond the traditional measures of body mass index (BMI) and dyslipidemia. In particular, we focused on the role of hepatic steatosis in obesity, and on the family history of patients with hyperlipidemia. We quantified circulating metabolites during an oral glucose tolerance test in BMI-discordant (ΔBMI ≥ 3 kg/m2) monozygotic twin pairs based on the presence of concomitant liver fat discordance. Liver fat -discordant cotwins exhibited greater putatively atherogenic differences in metabolomic parameters across a wide range of molecular classes, including lipoproteins, fatty acids, amino acids and glycoproteins. We also observed several putatively atherogenic differences between liver fat -concordant twin pairs, suggesting that increased BMI without concomitant liver fat accumulation may not be entirely neutral with respect to CVD risk. We performed the first comprehensive genotyping analysis of familial combined hyperlipidemia (FCH), a common familial hyperlipidemia typically characterized by elevations in total cholesterol or triglycerides. We observed rare high-impact variants in the APOE or APOA5 genes in only a few (3%) of hyperlipidemic family members. Almost a third of hyperlipidemic family members had elevated polygenic burden for LDL-C or triglycerides, similar to population samples with comparable lipid levels. Next, we estimated incident CVD risk in an overlapping cohort of hyperlipidemic families. We focused on common familial hyperlipidemias characterized by high LDL cholesterol or triglyceride levels after excluding individuals with monogenic FH. In our study, such familial hyperlipidemias conferred increased coronary artery disease and CVD risk, but the elevation in risk was similar to that observed in population-ascertained hyperlipidemias. Additionally, we observed highly similar lipidomic profiles consisting of 151 circulating lipid species between individuals with familial and population-ascertained hyperlipidemias. Our results add to existing support for hepatic steatosis as a more discerning stratifying CVD risk factor among individuals with increased BMI. Our findings on FCH and familial aggregation of high LDL cholesterol or triglyceride levels suggest that they share similar and overlapping pathophysiology with common population-ascertained hyperlipidemias, and may not confer differential CVD risk.

KW - Dyslipidemias

KW - +genetics

KW - +metabolism

KW - Liver

KW - Adiposity

KW - Hyperlipidemia, Familial Combined

KW - Hyperlipidemias

KW - Atherosclerosis

KW - Biomarkers

KW - Body Mass Index

KW - Cardiovascular Diseases

KW - Cholesterol

KW - Coronary Artery Disease

KW - Lipids

KW - Obesity

KW - Risk Assessment

KW - Risk Factors

KW - Triglycerides

KW - Twins, Monozygotic

KW - 3121 Internal medicine

KW - 3111 Biomedicine

KW - 1184 Genetics, developmental biology, physiology

M3 - Doctoral Thesis

SN - 978-951-51-5564-1

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - Helsingin yliopisto

CY - Helsinki

ER -

Rämö J. Genomic, metabolomic and clinical profiling of dyslipidemia in families. Helsinki: Helsingin yliopisto, 2019. 140 s. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 76/2019).